Stem cells have a capacity both for self-renewal and the generation of differentiated cell types. This pluripotentiality makes stem cells unique. In addition to studying the important normal function of stem cells in the regeneration of tissues, researchers have further sought to exploit the potential of in situ and/or exogenous stem cells for the treatment of a variety of disorders. While early, embryonic stem cells have generated considerable interest, the stem cells resident in adult tissues may also provide an important source of regenerative capacity.
These somatic, or adult, stem cells are undifferentiated cells that reside in differentiated tissues, and have the properties of self-renewal and generation of differentiated cell types. The differentiated cell types may include all or some of the specialized cells in the tissue. For example, hematopoietic stem cells give rise to all hematopoietic lineages, but do not seem to give rise to stromal and other cells found in the bone marrow. Sources of somatic stem cells include bone marrow, blood, the cornea and the retina of the eye, brain, skeletal muscle, dental pulp, liver, skin, the lining of the gastrointestinal tract, and pancreas. Adult stem cells are usually quite sparse. Often they are difficult to identify, isolate, and purify. Often, somatic stem cells are quiescient until stimulated by the appropriate growth signals.
Progenitor or precursor cells are similar to stem cells, but are usually considered to be distinct by virtue of lacking the capacity for self-renewal. Researchers often distinguish precursor/progenitor cells from stem cells in the following way: when a stem cell divides, one of the two new cells is often a stem cell capable of replicating itself again. In contrast, when a progenitor/precursor cell divides, it can form more progenitor/precursor cells or it can form two specialized cells, neither of which is capable of replicating itself. Progenitor/precursor cells can replace cells that are damaged or dead, thus maintaining the integrity and functions of a tissue such as liver or brain.
Stem cells from bone marrow are widely studied. Currently, they are used clinically to restore various blood and immune components to the bone marrow via transplantation. There are two major types of stem cells found in bone: hematopoietic stem cells that form blood and immune cells, and stromal (mesenchymal) stem cells that normally form bone, cartilage, and fat. The restricted capacity of hematopoietic stem cells to grow in large numbers and remain undifferentiated in the culture dish is a major limitation to their broader use for research and transplantation studies.
Muscle tissue in adult vertebrates regenerates from reserve myoblasts called satellite cells. Satellite cells are distributed throughout muscle tissue and are mitotically quiescent in the absence of injury or disease. Following recovery from damage due to injury or disease or in response to stimuli for growth or hypertrophy, satellite cells reenter the cell cycle, proliferate and enter existing muscle fibers or undergo differentiation into multinucleate myotubes, which form new muscle fiber. The myoblasts ultimately yield replacement muscle fibers or fuse into existing muscle fibers, thereby increasing fiber girth by the synthesis of contractile apparatus components. This process is illustrated, for example, by the nearly complete regeneration that occurs in mammals following induced muscle fiber degeneration or injury; the muscle progenitor cells proliferate and fuse together regenerating muscle fibers.
An important aspect of stem cell biology is the effect of aging. Many tissues of the major organ systems are composed of long-lived cells that are normally replaced infrequently, if at all. Therefore, such cells persist for significant portions of a mammal's lifespan. The functional activity of these cells changes over time in a process that is generally referred to as aging and, as most age-related changes in cells result in reduced functional viability, this is harmful.
The aging of stem cell populations has been documented for a number of systems. For example, the hematopoietic stem cell population, while able to maintain normal blood cell counts throughout life, in old age can lack the functional reserves to produce large numbers of progeny. It has been shown by Geiger & Van Zant (2002) Nature Immunology 3:329-333 that the number of HSC and progenitor cells does not decline dramatically in old age, and may actually increase. It was suggested that the important effects of aging may be on stem cell quality rather than quantity.
The age-related decrease in central nervous system remyelination efficiency has been attributed to an impairment of oligodendrocyte progenitor cell recruitment and differentiation, Sim et al. (2002) J. Neurosci. 22(7):2451-9. The progenitor cell response during remyelination of focal, toxin-induced CNS demyelination in young and old rats was compared and found to be delayed with aged animals.
Similarly, there is a decline in muscle bulk and performance associated with normal aging, resulting from gradual loss of both motor nerves and muscle fibers during senescence. Although skeletal muscle has the capacity to regenerate itself, this process is not activated in the elderly. It has been suggested that age-related changes within skeletal muscle tissue and the host environment affect the proliferation and fusion of myoblasts in response to injury in old animals.
The adverse effects of aging include deterioration in the ability of somatic stem cells to regenerate differentiated cells in multiple different tissues. Methods of increasing the ability of aged stem cell to regenerate tissue are of enormous clinical interest.